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An intrinsic tumor-suppression mechanism mediated by steroid hormone in Drosophila

ABSTRACT: Polycomb group (PcG) proteins are evolutionarily conserved epigenetic regulators that mediate histone modifications and suppress target gene expression, therefore establish and maintain cellular memory during development1-3. Deregulation of PcG genes is associated with various human cancers, but the mechanisms are incompletely understood4. Polyhomeotic (Ph), one of the Drosophila PcG proteins, can act as a tumor suppressor in larval imaginal discs5, 6. Cells mutant for ph overgrow and give rise to neoplastic tumors during larval development6. Here we report an intrinsic tumor-suppression mechanism mediated by the steroid hormone ecdysone in Drosophila. During metamorphosis, ecdysone transforms tumorigenic ph mutant cells into non-tumorigenic cells, thereby suppressing the malignant growth in adult flies. We demonstrate ecdysone exerts its function by inducing the expression of microRNA lethal-7 (let-7), which suppresses its target gene chinmo, to inhibit the tumorigenic growth of ph mutant cells. Furthermore, we show let-7 can also suppress the overgrowth of brain tumors in brain tumor (brat) mutant flies, indicating this intrinsic mechanism is functional in different tissues to suppress neoplastic growth. As let-7 is highly conserved among metazoans, our findings will be relevant for mechanistic studies and therapeutic applications in human cancers.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE101455 | GEO | 2018/08/20

REPOSITORIES: GEO

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Project description:Molting is an important physiological process in the larval stage of Bombyx mori and is controlled by various hormones and peptides. The silkworm mutant that exhibits the phenotype of non-molting in the 2nd instar (nm2) is incapable of molting in the 2nd instar and dies after seven or more days. The ecdysone titer in the nm2 mutant is lower than that in the wildtype, and the mutant can be rescued by feeding with 20E and cholesterol. The results of positional cloning indicated that structural alteration of BmCPG10 is responsible for the phenotype of the nm2 mutant. To explore the possible relationship between BmCPG10 and the ecdysone titer as well as the genes affected by BmCPG10, digital gene expression (DGE) profile analysis was conducted in the nm2 mutant, with the wildtype strain C603 serving as the control. The results revealed 1727 differentially expressed genes, among which 651 genes were upregulated and 1076 were downregulated in nm2. BLASTGO analysis showed that these differentially expressed genes were involved in various biological processes, cellular components and molecular functions. KEGG analysis indicated an enrichment of these differentially expressed genes in 240 pathways, including metabolic pathways, pancreatic secretion, protein digestion and absorption, fat digestion and absorption and glycerolipid metabolism. To verify the accuracy of the DGE results, quantitative reverse transcription PCR (qRT-PCR) was performed, focusing on key genes in several related pathways, and the results were highly consistent with the DGE results. Our findings indicated significant differences in cuticular protein genes, ecdysone biosynthesis genes and ecdysone-related nuclear receptors genes, but no significant difference in juvenile hormone and chitin biosynthesis genes was detected. Considering the physiological characteristics of nm2 together with the results of DGE analysis, we speculate that there may be a relationship between BmCPG10 and ecdysone. In the mutant, the original function of BmCPG10 was lost due to the change in its protein structure. It appeared that BmCPG10 might influence the synthesis of ecdysone by controlling the production of substrate cholesterol. However, under a low titer of ecdysone, the expression of BmCPG10 was affected, as one of a series of effectors of the ecdysone signaling pathway. Blocking ecdysone biosynthesis resulted in non-molting silkworms and the formation of the nm2 mutant.

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An intrinsic tumor-suppression mechanism mediated by steroid hormone in Drosophila

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